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Clinical Observations |
1 Department of Radiology, University of California Davis Medical Center, 4860 Y
St., Ste. 3100, Sacramento, CA 95817.
2 Department of Dermatology, University of California Davis Medical Center,
Sacramento, CA.
3 Department of Pathology, University of California Davis Medical Center,
Sacramento, CA.
4 Department of Pharmacology, University of California Davis Medical Center,
Sacramento, CA.
Received February 24, 2005;
accepted after revision April 11, 2005.
Address correspondence to R. W. Katzberg
(richard.katzberg{at}ucdmc.ucdavis.edu).
Abstract
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CONCLUSION. Radiologists and referring clinicians need to be aware of late adverse reactions to the administration of contrast media and to distinguish these from other possible causes.
Keywords: contrast media • CT
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Twenty-one hours after the chest CTA, and after hospitalization and heparinization, the patient received another 150 mL of iohexol (nonionic monomer; 300 mg I/mL) for a pelvic CTA to assess for pelvic blood clots as the source of the emboli. The examination was performed without any immediate adverse event. The next day, 14 hours after the pelvic CTA and 60 hours after the chest CTA, the patient awakened with itching on her back and with the onset of a rash. Over the course of the next 2 hours, a symmetric generalized skin eruption evolved from her trunk extending to her extremities. The rash and pruritus continued to worsen for 6 days and was associated with an eosinophilia (absolute eosinophils, 0.7; normal range, 0.0-0.3 x 1,000/mm) [3]. Over the next 7 days and as the rash began to subside (Fig. 1), desquamation began over her entire body, even in areas that had not shown the obvious rash. The desquamation continued for approximately another week for which the patient took diphenhydramine for symptomatic relief. The rash was initially thought to be secondary to a candidal infection, and the patient was started on IV fluconazole. A dermatology consultant reported a pustular eruption involving the trunk and skin folds, possibly representing acute generalized exanthematous pustulosis. A trephine (punch) biopsy was obtained from the abdomen approximately 48 hours after the onset of skin lesions. Because the pustular rash did not improve with antifungal therapy and the PAS stain from the skin biopsy was negative for fungal elements, the patient's signs and symptoms of acute generalized exanthematous pustulosis were initially thought to be secondary to a drug reaction to low molecular weight heparin. Heparin was stopped, and anticoagulation was continued with the direct thrombin inhibitor lepirudin. The patient's remaining hospital course was uneventful, and she was discharged to home.
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Routine (H and E) stained sections (Figs. 2A, 2B, and 2C) from the abdominal skin biopsy revealed subcorneal pustules, rare single apoptotic keratinocytes, and perivascular and interstitial lymphocytes with scattered eosinophils and neutrophils. These findings were interpreted as consistent with a pustular drug reaction, specifically acute generalized exanthematous pustulosis [3].
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Patient 2
A chest CTA was performed on a 30-year-old woman as part of an extensive
evaluation of chest pressures and paresthesias. A total of 150 mL iodixanol
(320 mg I/mL) was injected via an upper-extremity IV at 4 mL/s. The injection
was performed without any immediate adverse event. Approximately 48 hours
after the chest CTA, the patient, while at home, noticed a generalized
confluent skin rash involving her arms and legs, abdomen, thorax, palms, and
soles. The primary lesions were small 1- to 2-mm raised red papules that the
patient described as "pimplelike"
(Fig. 3). The pruritic rash was
accentuated in the groin and medial thighs. A biopsy was not acquired. Both
the pruritus and the rash lasted for approximately 2 weeks. The patient's
palms and soles "peeled" at approximately 2-4 weeks compatible
with a resolving pustular eruption. The patient had no known medication
allergies. No history of previous administration of IV contrast media was
noted.
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Yoshikawa [1] performed a prospective study of late adverse reactions to a low osmolal nonionic monomer in 2,382 subjects who underwent CT in Japan. Overall, 2.4% of patients experienced a rash occurring in 30 minutes to 2 days after the administration of the contrast material.
Sutton et al. [4, 5] performed two successive studies in Middlesbrough, England, of 2,001 and 2,108 patients, respectively, after cardiac catheterization and found late skin reactions with the isotonic dimer iodixanol in 10.4% in the first study and 12.2% in the second study.
Vernassiere et al. [6] reported 15 patients in France having experienced delayed reactions after receiving iodinated contrast media. Eleven of the 15 cases (73%) had received iodixanol; one patient (6.7%), iohexol; one patient (6.7%), ioxaglate (ionic dimer); one patient (6.7%), iobitridol (nonionic monomer); one patient (6.7%), iomeprol (nonionic monomer); and one patient (6.7%), not stated. The mean duration of the rash was 4.8 days (1-20 days). Histologic examination performed in five patients revealed nonspecific findings of perivascular dermatitis, with variable features including dermal edema, dermal eosinophils, and epidermal spongiosis. The clinical features and histologic findings favored a T-cell hypersensitivity.
Our department uses four CT scanners and performs on average 75 enhanced CT scans per day. We have a level 1 trauma center and an overall imaging procedure volume of approximately 360,000 examinations per year. If the survey by Yoshikawa [1] is used as a guide, we would conservatively estimate a delayed adverse reaction rate of approximately 2%. This would equate to an occurrence of approximately 10 delayed adverse reactions per week (0.02 x 75 contrast examinations/d x 7 days). A prospective study is needed to assess the clinical significance of these side effects and the prevalence of acute generalized exanthematous pustulosis.
Speck et al. [7] reported a prolonged dwell time for a nonionic dimer in the rat kidney that was 40 times the concentration in milligrams of iodine per gram of tissue compared with a nonionic monomer at 7 days postadministration. The dose was 1 gram of iodine per kilogram. Speck et al. [8] later noted an increase in concentration of nonionic dimers in the skin of rats investigated 3 days after the IV injection in comparison to nonionic monomers. These studies were performed to investigate the pathophysiology of delayed hypersensitivity to contrast media. The authors postulated that iodinated contrast media may form molecular agglomerates that are larger and more stable the lower the osmolality and the higher the viscosity as occurs with the nonionic isotonic dimers. It was further postulated that these intravascular agglomerates may persist for some seconds or minutes despite the rapid dilution after the injection. During this period of time, the agent may enter the cells and stimulate or mediate a delayed hypersensitivity irrespective of the amount of contrast material that has already been excreted at the time of the late reaction.
There are no well-established specific risk factors for delayed adverse reactions to contrast media other than those already known for acute reactions. These include a prior reaction to contrast media, multiple allergies, and chronic bronchial asthma. Female sex and age between 40 and 60 years have also been suggested [2, 7].
Treatment of cutaneous reactions is directed toward symptomatic relief and establishment of the cause [3]. Antihistamines such as diphenhydramine or hydroxyzine for pruritus, topical corticosteroids and emollients for cutaneous reactions, and careful monitoring for any systemic signs or symptoms of hepatic, renal, joint, respiratory, hematologic, and neurologic changes are recommended. Fever, malaise, pharyngitis, and other systemic symptoms or signs should be investigated. A usual laboratory screen would include a full blood count, liver and renal function tests, and urinalysis.
It can be difficult to distinguish the causative agent of a skin reaction between one of the most commonly used drugs, such as contrast media, from potential but life-saving therapeutic agents (such as heparin in our case). The first responsibility is to recognize that intravascular iodinated contrast media can be an important cause of delayed adverse reactions. Outpatients and referring clinicians should be instructed on how to recognize a reaction and what steps to take should it occur. Once a delayed reaction begins, close patient monitoring and reassurance are important. Fortunately, most of these responses are minor and without serious sequelae. Conversely, not all adverse events after a patient has received contrast media are related to the contrast medium itself, and a detailed evaluation of other causes should be initiated.
Based on published reports, cutaneous delayed adverse reactions associated with the administration of iodinated contrast media may exhibit a variety of presentations, including maculopapular (morbilliform), macular (rubellalike), papular, and pustular eruptions [6]. The histopathologic features of cutaneous delayed adverse reactions appear to correlate with the clinical morphology. The striking pustular eruption displayed by our first case clinically and histopathologically is consistent with acute generalized exanthematous pustulosis. Acute generalized exanthematous pustulosis is generally attributed to drugs, particularly ß-lactam, sulfonamide, and macrolide antibiotics, or, in a minority of cases, to viral infection [9].
The mechanism of subcorneal pustule formation in acute generalized exanthematous pustulosis appears to be a T-cell-mediated process. In response to stimulation by antigen-presenting cells in the skin (e.g., Langerhans cells) or lymph node, drug-specific cytotoxic T cells (CD8 positive) and also helper T cells (CD4 positive) accumulate in the epidermis and upper dermis. Cytotoxic T cells primarily mediate tissue destruction, and helper T cells primarily accumulate within intraepidermal vesicles. Secretion of the chemokine CXCL8 (also known as interleukin-8) and other cytokines such as GM-CSF by helper T cells may mediate the accumulation of neutrophils within subcorneal vesicles, resulting in the clinical appearance of pustules [10, 11].
In summary, radiologists and referring clinicians need to be aware of the existence of delayed adverse reactions to contrast media and to distinguish these reactions from other disease entities.
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  A. A. Hammerbeck, N. H. Daniels, and J. P. Callen Ioversol-Induced Acute Generalized Exanthematous Pustulosis: A Case Report Arch Dermatol, June 1, 2009; 145(6): 683 - 687. [Abstract] [Full Text] [PDF]
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